Alexis Magre

Background: Anti-N-Methyl-D-Aspartate receptor (anti-NMDAR) encephalitis is characterized by an acute decline in cognitive function, psychiatric symptoms, seizures, and movement disorders.^1-3  The main pathologic mechanism of anti-NMDAR encephalitis is internalization of NMDARs after autoantibodies bind to the GluN1 subunit which causes subsequent neuronal hypoactivity.^2,3 There are few approved therapies for anti-NMDAR encephalitis, including high dose steroids, plasma exchange (PE), and intravenous immunoglobulin (IVIG), which has led to variability in how the illness is treated.² This is partially due to the pathological mechanisms of anti-NMDAR encephalitis not being fully understood so further investigation is needed.^4-8 Additionally treatment is slow and the blood brain barrier could affect the efficaciousness of PE and IVIG.² Some research has shown reduced internalization of NMDARs when associated with proteins EphB2 and PSD-19, which poses potential novel therapeutic targets for anti-NMDAR encephalitis.^6-8

Objective: This narrative review further characterizes the internalization of NMDARs and explores potential new therapeutic targets, EphB2 and PSD-95, that may help to stabilize NMDARs on the neural membrane.

Search Methods: PubMed and EBSCOHost databases were used to conduct online searches from 2018 to 2024. The following keywords were used: “anti-NMDAR encephalitis,” “NMDAR autoimmune encephalitis,” and “NMDAR autoantibodies.”

Results: It was found that internalization of NMDARs was time and temperature dependent.⁴ Internalization began 10 minutes after antibodies to GluN1 and GluN2B were introduced, and all the NMDA-type GluR were in the cytoplasm after 60 minutes.⁴ Additionally, all NMDA-type GluRs were internalized at 37°C but none moved to the cytosol at 4°C.⁴  A mouse model was studied to further characterize the behavioral symptoms of anti-NMDAR encephalitis.⁵ Total horizontal movement distance and time in the central area were significantly decreased in the immunized group compared to the control.⁵ This demonstrated depressive or anxious behavior in the immunized group compared to the control group.⁵ The positive surface charge of the N-terminal domain hinge region mediated the interaction between NMDARs and EphB2. Each amino acid forming the positive region was mutated and there was a significant change in surface potential in the hinge region of all the mutants.⁶  Interactions between EphB2 and GluN1  were reduced in all the mutants compared to the wild type.⁶  Stochastic optical reconstruction microscopy (STORM) was used to show how EphB2 can slow receptor internalization of NMDARs when exposed to autoantibodies.⁷ Alterations of the NMDARs from the antibodies on the neural membrane were reduced in both GluN1 and GluN2B subunits when interacting with EphB2.⁷ An assay was performed where the autoantibodies were pH rhodamine labeled.⁸ NMDAR-antibody complexes that were internalized showed fluorescence due to the low pH in lysosomes.⁸ Co-expression of GluN1/GluN2B with PSD-95 significantly reduced the fluorescence intensity.⁸

Conclusions: Studies have found that when NMDARs interact with EphB2 and PSD-95 there is significantly less internalization of NMDARs when exposed to autoantibodies. Stabilization of NMDARs by these proteins could have therapeutic implications for patients suffering from NMDAR autoimmune encephalitis.

Works Cited:

1. Huang Q, Xie Y, Hu Z, Tang X. Anti-N-methyl-D-aspartate receptor encephalitis: A review of pathogenic mechanisms, treatment, prognosis. Brain Research. 2020;1727:146549. Published 2020 Jan 15. doi: 10.1016/j.brainres.2019.146549. https://www.sciencedirect.com/science/article/pii/S0006899319306031#s0010
2. Lin K, Lin J. Neurocritical care for Anti-NMDA receptor encephalitis. Biomedical Journal. 2020;43(3):251-258. Published 2020 Aug 10. doi: 10.1016/j.bj.2020.04.002. https://www.sciencedirect.com/science/article/pii/S2319417020300342#sec1
3. Nguyen L, Wang C. Anti-NMDA Receptor Autoimmune Encephalitis: Diagnosis and Management Strategies. Int J Gen Med. 2023;16:7-21. Published 2023 Jan 4. doi: 10.2147/IJGM.S397429. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9826635/
4. Takahashi Y. et al. Characteristics of internalization of NMDA-type GluRs with antibodies to GluN1 and GluN2B. Journal of Neuroimmunology. 2020;349. Published 2020 Dec. 15. doi: 10.1016/j.jneuroim.2020.577427. https://www.sciencedirect.com/science/article/pii/S0165572820306883
5. Yu L. et al. Autoimmune receptor encephalitis in ApoE^/mice induced by active immunization with NMDA1. Mol Med Rep. 28;6(233). Published 2023 Dec. doi: 10.3892/mmr.2023.13120.https://pubmed.ncbi.nlm.nih.gov/37921064/
6. Washburn H. et al. Positive surface charge of GluN1 N-terminus mediates the direct interaction with EphB2 and NMDAR mobility. Nature Communications. 2020;11(570). Published 2020 Jan. 29. doi: 10.1038/s41467-020-14345-6.https://www.nature.com/articles/s41467-020-14345-6
7. Ladépêche L. et al. NMDA Receptor Autoantibodies in Autoimmune Encephalitis Cause a Subunit-Specific Nanoscale Redistribution of NMDA Receptors. Cell Reports. 2018;23(13):3759-3768. Published 2018 June 26. doi: 10.1016/j.celrep.2018.05.096.https://www.sciencedirect.com/science/article/pii/S2211124718308921
8. Amedonu E et al. An Assay to Determine Mechanisms of Rapid Autoantibody-Induced Neurotransmitter Receptor Endocytosis and Vesicular Trafficking in Autoimmune Encephalitis. Frontiers in Neurology. 2019;10. Published 2019 Feb. doi: 10.3389/fneur.2019.00178https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2019.00178